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Updated: Jun 29, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Feedback activation of CD73-Adenosine axis attenuates the antitumor immunity of STING pathway

Nannan Fu1, Ziang Zhang1, Junmin Quan1

  • 1State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.

Biochemical and Biophysical Research Communications
|March 26, 2024
PubMed

Insights

STING activation boosts CD73 and adenosine, a feedback loop. Combining STING agonists with CD73 inhibitors effectively inhibits tumor growth by modulating immune cells in the tumor microenvironment.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is vital for innate immunity and a promising cancer therapy target.
  • Tumor treatment targeting the cGAS-STING pathway faces challenges due to complex feedback mechanisms.

Purpose of the Study:

  • To investigate the feedback mechanisms of the cGAS-STING pathway in cancer.
  • To explore the therapeutic potential of combining STING agonists with CD73 inhibitors for cancer immunotherapy.

Main Methods:

  • Assessed STING activation effects on CD73 expression and adenosine production in immune and cancer cells.
  • Investigated the role of the type I interferon (IFN)/IFN-alpha/beta receptor (IFNAR) axis in STING-induced CD73 feedback.
  • Evaluated the efficacy of combining STING agonists with anti-CD73 monoclonal antibodies (mAbs) in a tumor model.

Main Results:

  • STING activation was found to enhance CD73 expression and adenosine production.
  • This feedback activation of CD73 was dependent on the type I IFN/IFNAR signaling pathway induced by STING.
  • Combination therapy significantly inhibited tumor growth by increasing CD8+ T cell infiltration and decreasing regulatory T cell (Treg) accumulation.

Conclusions:

  • STING activation induces a CD73-adenosine feedback loop mediated by type I IFN/IFNAR signaling.
  • Combining STING agonists with CD73 inhibitors offers a promising strategy for cancer immunotherapy by reprogramming the tumor microenvironment.
Keywords:
AdenosineCD73ImmunotherapyInnate immunitycGAS-STING

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